WO1990015818A1 - Synthetic peptides for use in thrombus detection - Google Patents

Synthetic peptides for use in thrombus detection Download PDF

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Publication number
WO1990015818A1
WO1990015818A1 PCT/GB1990/000933 GB9000933W WO9015818A1 WO 1990015818 A1 WO1990015818 A1 WO 1990015818A1 GB 9000933 W GB9000933 W GB 9000933W WO 9015818 A1 WO9015818 A1 WO 9015818A1
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Prior art keywords
rgd
peptide
peptides
binding site
thrombus
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Application number
PCT/GB1990/000933
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French (fr)
Inventor
Alan William John Stuttle
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Antisoma Limited
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Application filed by Antisoma Limited filed Critical Antisoma Limited
Priority to EP90909765A priority Critical patent/EP0429626B2/en
Priority to DE69026685T priority patent/DE69026685T3/en
Priority to DK90909765T priority patent/DK0429626T4/en
Publication of WO1990015818A1 publication Critical patent/WO1990015818A1/en
Priority to GB9103416A priority patent/GB2241243B/en
Priority to US08/057,045 priority patent/US5395609A/en
Priority to US08/816,922 priority patent/US5843402A/en
Priority to US09/010,290 priority patent/US6217846B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/082—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being a RGD-containing peptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates to the development and use of synthetic pep tides for thrombus detection both in human beings and animals, but primarily, of course, in the detection of human disease.
  • the Method and the synthetic peptides used therein are also useful in targetting other sites in vivo, eg, cell adhesion molecules (CAMs) and tumors, containing an RGD binding site.
  • CAMs cell adhesion molecules
  • RGDS sequence has been shown to occur in fibrinogen, fibronectin and von Willebrand factor. Receptors for these proteins are expressed on the platelet membrane surface following platelet activation. Cross-linking of platelets via these cytoadhesive proteins accounts for the platelet-platelet interactions within a thrombus. It has also been demonstrated that RGDS containing synthetic peptides are capable of inhibiting platelet aggregation in vitro. This would suggest a specific interaction with the GP Hb/IIIa (glycoprotein fibrinogen receptor) complex present on the platelet mem ⁇ brane surface, which contains the fibrinogen binding domains.
  • GP Hb/IIIa glycoprotein fibrinogen receptor
  • the present invention involves a novel approach to in vivo thrombus detection and which comprises the intravenous injection into the patient (which term herein includes both humans and animals, unless the context requires otherwise) of a radioactively labelled synthetic peptide having therein an RGD (Arg-Gly-Asp) -containing sequence, preferably an RGDS (Arg-Gly-Asp-Ser) or RGDF (Arg-Gly-Asp-Phe)-containing sequence having a specific binding affinity for the platelet GP Hb/IIIa complex, and detecting the presence, if present, of the bound label on the thrombus.
  • RGD Arg-Gly-Asp
  • RGDS Arg-Gly-Asp-Ser
  • RGDF Arg-Gly-Asp-Phe
  • Present methods of thrombus detection using labelled antibodies require several hours due to the slow rate of diffusion of the antibody through the system; using labelled peptides in accordance with the present invention is expected to enable thrombus detection in a matter of minutes, thus greatly facilita ⁇ ting diagnosis and treatment, and at a very early stage.
  • a synthetic peptide containing the sequence RGD preferably as RGDS or RGDF, and labelled with a radio ⁇ active label.
  • Suitable radioactive labels for use in the construction of such radioactively labelled peptides include: Tc 99m , 1*23 an( j ⁇ n m, and will be attached to the synthetic peptide in known manner, for example, via a cystine residue in the synthetic peptide.
  • Other suitable techniques are described in Science, 220, 613-615; Int. J. Nucl. Med. Biol., 12, 3-8; J. Nucl. Med., 27, 27, 685-693 and J. Nucl. Med., 26, 293-299.
  • Suitable peptides containing an RGD sequence preferably an RGDS or RGDF are available from a variety of different sources, or can be manufactured quite readily using conventional peptide synthesis procedures, and, in particular, using a conventional peptide synthesiser.
  • a diagnostic reagent for in vivo thrombus detection comprising a parenterally administrable solution of the radioactively labelled peptide containing an RGD sequence and a parenterally administrable carrier, and a method of in vivo thrombus detection which comprises intravenously administering a radioactively labelled peptide containing and RGD sequence capable of binding to RGD binding sites on platelets in the thrombus and radiographically detecting the accumulated bound peptide
  • the invention also extends to the use of the radioactively labelled peptides in in vivo localisation on to the RGD binding sites of CAMs.
  • amino acid sequences referred to herein are identified by either their three letter abbreviations or single letter codes, as follows:
  • FIG. 1 is a radiograph taken of a rabbit following intravenous administration of a radioactively labelled peptide according to this invention, and showing the localisation of the peptide in an artificially induced thrombus in the left ear.
  • studies have been conducted using four peptides (RGDSY, RGDFY, RGDSYC and RGDSCRGDSY) to evaluate their potential as thrombus imaging agents.
  • the second study involved radiodination of RGDSY, RGDFY, RGDSYC and RGDSCRGDSY with subsequent analysis of their ability to bind activated platelets in whole blood.
  • the results indicate that all four peptides can bind platelets in ADP stimulated blood and that higher incorporation can be achieved in clotted blood.
  • the above results demonstrate the applicability of the invention over a range of synthetic peptides of different sizes all containing an RGD sequence.
  • the actual length of the peptides is not critical, but for practical purposes the chain lengths may range from 3 to 10 peptide units, preferably 4 to 10 and, as already indicated, either consisting of or comprising an RGDS or RGDF sequence.
  • Many such synthetic peptides are already available as known commercial products. Where not so available they can be readily synthesised by known peptide syntheses and/or using known peptide synthesisers.
  • radioactively labelled peptides can be radioactively labelled by known techniques, for example, by iodination with I 1 23 0 f a terminal tyrosine (Y) unit incorporated into the peptide.
  • Y terminal tyrosine
  • lodogen tubes were prepared by dissolving lodogen (1, 3, 4, 6-Tetrachloro- 3o( , 6 -diphenylglycouril) in chloroform at a concentration of lmg.ml" 1 . Aliquots of 50 ⁇ l (50 ⁇ g lodogen) were dispensed into polypropylene cryo-tubes and the chloroform evaporated to dryness. These tubes were then stored dessicated at -20 °C until required.
  • peptides Prior to radiolabelling the peptides were dissolved in phosphate buffered saline (PBS) at a concentration of ⁇ O ⁇ g.ml" 1 .
  • PBS phosphate buffered saline
  • RGDSYC and RGDSCRGDSY were first dissolved in a small volume of dimethyl sulphoxide (DMSO) such that the final concentration of DMSO in PBS was 1% v/v.
  • DMSO dimethyl sulphoxide
  • lodogen tubes were equilibrated to room temperature before the addition of 200 ⁇ l peptide solution and 1-lOul of 123j (j n a q Ue0US solution). The reation mixture was then left for 15min at room temperature with occasional shaking. Following the incubation period the reaction mixture was removed and passed through a Sephadex G10 column which had been equilibrated with PBS. The column, which separates radiolabelled peptide from free iodine was eluted with PBS and 2 ml fractions collected. Radioactivity in the fractions was measured and the eluted peptides, represented by the first radioactive peak from the column, collected and stored at 4°C until required.
  • a male New Zealand White rabbit (3kg) was sedated by intramuscular injection of Hypnor (0.4ml.kg _1 ) and then anaesthetised by intravenous injection of Midazolam (2mg.kg _1 ).
  • the rabbit was radiographed and the resulting radiograph is presented in the accompanying figure. As indicated by the radiograph, there was rapid uptake of the peptide by a thromus in the jugular vein (arrow 1) and by multiple tiny thrombi in the left ear (arrow 2). The latter, in particular, demonstrates the possible utility of the invention in the detection of small thrombi in vivo and the possibility of early diagnosis and treatment.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Optics & Photonics (AREA)
  • Toxicology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Radioactively labelled peptides comprising oligopeptides of from 3 to 10 peptide units and containing the sequence RGD and particularly the oligopeptides RGDSY and RGDFY, are disclosed as in vivo thrombus, tumour or CAM markers for the in vivo diagnosis and detection of thrombi, tumours or CAM in mammals.

Description

SYNTHETIC PEPTIDES FOR USE IN THROMBUS DETECTION
This invention relates to the development and use of synthetic pep tides for thrombus detection both in human beings and animals, but primarily, of course, in the detection of human disease. The Method and the synthetic peptides used therein are also useful in targetting other sites in vivo, eg, cell adhesion molecules (CAMs) and tumors, containing an RGD binding site.
In 1984 Pierschbacher and Ruoslahti (Nature, 309, 30-33), showed evidence that the cell attachment activity of fibronectin could be mimicked by small synthetic peptide fragments. The amino acid sequence responsible for this activity was shown to be Arg-Gly-Asp-Ser (RGDS) and it was demonstrated that synthetic peptides containing this sequence were able to inhibit attachment of NRK cells (cells from a neuroblastoma cell line) to fibro¬ nectin coated substrates. The inhibition obtained with RGDS containing peptides was shown to be dose-related, whilst peptides which did not contain the RGDS sequence failed to inhibit cell attachment. The serine residue of the tetrapeptide has been shown to be non-essential, although only conser¬ vative substitutions may be made in order to retain biological activity.
The RGDS sequence has been shown to occur in fibrinogen, fibronectin and von Willebrand factor. Receptors for these proteins are expressed on the platelet membrane surface following platelet activation. Cross-linking of platelets via these cytoadhesive proteins accounts for the platelet-platelet interactions within a thrombus. It has also been demonstrated that RGDS containing synthetic peptides are capable of inhibiting platelet aggregation in vitro. This would suggest a specific interaction with the GP Hb/IIIa (glycoprotein fibrinogen receptor) complex present on the platelet mem¬ brane surface, which contains the fibrinogen binding domains. Extension of the RGDS sequence, by one amino acid residue at the carboxy and amino terminal, results in a ten-fold reduction in its biological activity, although further extension is not associated with a further reduction in binding capacity. Substitution of the serine residue by phenylalanine results in an anti-aggregatory peptide which is 4 to 5 times more potent than RGDS. There has also been suggestion that the residue corresponding to serine in the RGDS sequence may impart a degree of recognition specificity for different RjGDS receptors. This raises the possibility that both specificity and affinity could be modified by substitution around the RGD sequence. RGD binding sites are also known to occur on cell adhesion molecules (CAMs) and some tumors.
The present invention involves a novel approach to in vivo thrombus detection and which comprises the intravenous injection into the patient (which term herein includes both humans and animals, unless the context requires otherwise) of a radioactively labelled synthetic peptide having therein an RGD (Arg-Gly-Asp) -containing sequence, preferably an RGDS (Arg-Gly-Asp-Ser) or RGDF (Arg-Gly-Asp-Phe)-containing sequence having a specific binding affinity for the platelet GP Hb/IIIa complex, and detecting the presence, if present, of the bound label on the thrombus. Present methods of thrombus detection using labelled antibodies require several hours due to the slow rate of diffusion of the antibody through the system; using labelled peptides in accordance with the present invention is expected to enable thrombus detection in a matter of minutes, thus greatly facilita¬ ting diagnosis and treatment, and at a very early stage.
For use in that method of in vivo thrombus detection there is provided in accordance with the present invention a synthetic peptide containing the sequence RGD, preferably as RGDS or RGDF, and labelled with a radio¬ active label.
Suitable radioactive labels for use in the construction of such radioactively labelled peptides include: Tc99m, 1*23 an(j ιnm, and will be attached to the synthetic peptide in known manner, for example, via a cystine residue in the synthetic peptide. Other suitable techniques are described in Science, 220, 613-615; Int. J. Nucl. Med. Biol., 12, 3-8; J. Nucl. Med., 27, 27, 685-693 and J. Nucl. Med., 26, 293-299.
Subject to the dictates of suitability for parenteral administration and utility, i.e. high affinity and specificity for the GP Hb/IIIa complex, the precise amino acid sequence in terms of composition and length will not be particularly critical, although for practical reasons, e.g. economy and ease of synthesis, relatively short chain peptides will be preferred containing, for example, from 3 to 10 peptide units. Suitable peptides containing an RGD sequence, preferably an RGDS or RGDF are available from a variety of different sources, or can be manufactured quite readily using conventional peptide synthesis procedures, and, in particular, using a conventional peptide synthesiser.
Also included within the scope of this invention are a diagnostic reagent for in vivo thrombus detection comprising a parenterally administrable solution of the radioactively labelled peptide containing an RGD sequence and a parenterally administrable carrier, and a method of in vivo thrombus detection which comprises intravenously administering a radioactively labelled peptide containing and RGD sequence capable of binding to RGD binding sites on platelets in the thrombus and radiographically detecting the accumulated bound peptide
The invention also extends to the use of the radioactively labelled peptides in in vivo localisation on to the RGD binding sites of CAMs.
Before proceeding further with the detailed description of this invention, and for the avoidance of doubt, the amino acid sequences referred to herein are identified by either their three letter abbreviations or single letter codes, as follows:
arginine = arg. or R. aspartic acid = asp. or D. glycine = gly. or G. serine = ser. or S tyrosine = tyr. or Y phenylalanine = phe. or F cysteine = cys. or C
Reference is also made hereinafter to the accompanying figure, which is a radiograph taken of a rabbit following intravenous administration of a radioactively labelled peptide according to this invention, and showing the localisation of the peptide in an artificially induced thrombus in the left ear. Referring to the invention in slightly more detail, studies have been conducted using four peptides (RGDSY, RGDFY, RGDSYC and RGDSCRGDSY) to evaluate their potential as thrombus imaging agents.
The effect of these peptides on ADP-induced platelet aggregation was determined and compared with peptide RGDS which is known to inhibit platelet aggregation. The results (table 1) demonstrate that all four peptides studied are capable of inhibiting platelet aggregation at high concentrations and are virtually equipotent with RGDS. This suggests that inclusion of amino acids into these peptide sequences, to permit radio- labelling, does not destroy their ability to bind platelets (a prerequisite for thrombus imaging applications).
The second study involved radiodination of RGDSY, RGDFY, RGDSYC and RGDSCRGDSY with subsequent analysis of their ability to bind activated platelets in whole blood. The results (Table 2) indicate that all four peptides can bind platelets in ADP stimulated blood and that higher incorporation can be achieved in clotted blood.
One study was performed using RGDSY, labelled with the radioisotope iodine-123, injected into a rabbit who had a preformed thrombus in the microvasculature of the ear. The imaging studies, shown in the accom¬ panying figure demonstrates a rapid uptake onto this thrombus (within 2 minutes of injection), which persisted for the period of study (20 minutes).
These data demonstrate that the four peptides studied are capable of binding to platelets, can be radiolabelled with gamma-emitting isotopes and are incorporated into platelet aggregates in stimulated and clotted blood. This provides good potential for thrombus detection and diagnosis by these peptides in vivo which has been confirmed, in an experimental animal model, using one of the peptides.
Table 1 Inhibition of ADP (Ixl0-5M) -induced platelet aggregation by RGDS, RGDSY, RGDFY, RGDSYC and RGDSCRGDSY peptides. (peptide) percentage inhibition rnM RGDS RGDSY RGDFY RGDSYC RGDSCRGDSY
0.1 40/37 5/13 32 25 17
0.2 70/65 10/21 55 57
0.4 86/80 43/68 80 79
Table 2 Binding of radiolabeUed RGDSY, RGDFY, RGDSYC and RGDSCRGDSY peptides ro ADP stimulated and clotted blood.
(peptide) (bound peptide) ng ng RGDSY RGDFY RGDSYC RGDSCRGDSY
ADP Stimulated blood
1 0.05 0.01 0.03 0.01
10 0.64 1.00 0.94 0.85
100 9.80 4.46 9.85 9.07
Clotted Blood
1 0.27 0.41 0.18 0.28
10 0.85 2.14 2.26 2.64
100 17.27 18.12 27.08 29.33
The above results demonstrate the applicability of the invention over a range of synthetic peptides of different sizes all containing an RGD sequence. The actual length of the peptides is not critical, but for practical purposes the chain lengths may range from 3 to 10 peptide units, preferably 4 to 10 and, as already indicated, either consisting of or comprising an RGDS or RGDF sequence. Many such synthetic peptides are already available as known commercial products. Where not so available they can be readily synthesised by known peptide syntheses and/or using known peptide synthesisers. Similarlysaid synthetic peptides can be radioactively labelled by known techniques, for example, by iodination with I123 0f a terminal tyrosine (Y) unit incorporated into the peptide. The detailed preparation of radioactively labelled peptides according to this invention is illustrated by the following example
Example
Preparation of radioactively labelled (I123) RGDSY, RGDFY, RGDSYC and RGDSCRDSY
lodogen tubes were prepared by dissolving lodogen (1, 3, 4, 6-Tetrachloro- 3o( , 6 -diphenylglycouril) in chloroform at a concentration of lmg.ml"1. Aliquots of 50μl (50μg lodogen) were dispensed into polypropylene cryo-tubes and the chloroform evaporated to dryness. These tubes were then stored dessicated at -20 °C until required.
Prior to radiolabelling the peptides were dissolved in phosphate buffered saline (PBS) at a concentration of δOμg.ml"1. RGDSYC and RGDSCRGDSY were first dissolved in a small volume of dimethyl sulphoxide (DMSO) such that the final concentration of DMSO in PBS was 1% v/v.
lodogen tubes were equilibrated to room temperature before the addition of 200μl peptide solution and 1-lOul of 123j (jn aqUe0US solution). The reation mixture was then left for 15min at room temperature with occasional shaking. Following the incubation period the reaction mixture was removed and passed through a Sephadex G10 column which had been equilibrated with PBS. The column, which separates radiolabelled peptide from free iodine was eluted with PBS and 2 ml fractions collected. Radioactivity in the fractions was measured and the eluted peptides, represented by the first radioactive peak from the column, collected and stored at 4°C until required.
The utility of the radioactively labelled peptides in in vivo thrombus detection is illustrated by the following experiment. Experiment
Intravenous administsration of radioactively labelled (1*23) RGDSY to thrombitic rabbits
A male New Zealand White rabbit (3kg) was sedated by intramuscular injection of Hypnor (0.4ml.kg_1) and then anaesthetised by intravenous injection of Midazolam (2mg.kg_1).
Two permanent disc magnets were positioned externally in the region of the jugular vein and the rabbit was then injected with 0.2g carbonyl iron microspheres suspended in 1ml of contrast media (Omnipaque) via an artery of the left ear. This procedure causes mierothrombi in the capillary beds of the ear, whilst iron particles passing through the ear are trapped by the magnetic field and induce thrombus formation in the jugular vein. 123j_ RGDSY was injected intravenously into the contralateral ear 60min after injection of iron. Dynamic imaging by gamma camera was performed using a lmin frame rate for 20min with the camera positioned anteriorly to include both ears, head and neck regions in the field of view.
Following intravenous administration of the labelled peptide, the rabbit was radiographed and the resulting radiograph is presented in the accompanying figure. As indicated by the radiograph, there was rapid uptake of the peptide by a thromus in the jugular vein (arrow 1) and by multiple tiny thrombi in the left ear (arrow 2). The latter, in particular, demonstrates the possible utility of the invention in the detection of small thrombi in vivo and the possibility of early diagnosis and treatment.

Claims

Radioactively labelled peptides containing from 3 to 10 peptide units capable of binding in vivo to an RGD binding site, and containing^ in said 3 to 10 peptide units, the sequence arginine - glycine - aspartic acid (RGD).
Radioactively labelled peptides according to claim 1 consisting of or containing the sequence arginine - glycine - aspartic acid - serine (RGDS) or the sequence arginine - glycine - asapartie acid - phenylalanine (RGDF)
3 Radioactively labelled peptides according to claim 1 being specifically the peptides:
RGDSY, RGDFY, RGDSYC and RGDSCRGDSY
4. A radioactively-labelled peptide according to any one of claims 1 to 3, wherein the radioactive label is Tc99m, 1*23 or folll.
5. A diagnostic reagent for in vivo localisation on an RGD binding site comprising a parenterally administrable radioactively-labelled peptide containing an RGD sequence and a parenterally administrable carrier.
6 A diagnostic reagent according to claim 5, wherein said RGD binding site is a platelet binding site.
7 A diagnostic reagent according to claim 6, wherein said RGD binding site is a thrombus.
8 A diagnostic reagent according to claim 5, wherein said RGD binding site is of a cell adhesion molecule.
9. A diagnostic reagent according to claim 5, wherein said RGD binding site is on a tumor.
10. A diagnostic reagent according to any of claims 5 - 9, wherein the radioactively labelled peptide is a compound according to any of the claims 1 - 4 .
11 A method of in vivo thrombus detection which comprises intravenously administering a radio actively labelled peptide containing and RGD sequence capable of binding to RGD binding sites on platelets in the thrombus and radiographically detecting the accumulated bound peptide.
PCT/GB1990/000933 1989-06-19 1990-06-18 Synthetic peptides for use in thrombus detection WO1990015818A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP90909765A EP0429626B2 (en) 1989-06-19 1990-06-18 Synthetic peptides for use in vivo in thrombus detection
DE69026685T DE69026685T3 (en) 1989-06-19 1990-06-18 Synthetic peptides for the detection of thromboses
DK90909765T DK0429626T4 (en) 1989-06-19 1990-06-18 Synthetic peptides for the detection of thrombi
GB9103416A GB2241243B (en) 1989-06-19 1991-02-19 Rgd-containing oligopeptides for use in thrombus and tumour detection
US08/057,045 US5395609A (en) 1989-06-19 1993-05-03 Synthetic peptides for use in tumor detection
US08/816,922 US5843402A (en) 1989-06-19 1997-03-12 Synthetic peptides for use in thrombus detection
US09/010,290 US6217846B1 (en) 1989-06-19 1998-01-21 Synthetic peptides for use in thrombus detection

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8914020.6 1989-06-19
GB898914020A GB8914020D0 (en) 1989-06-19 1989-06-19 Synthetic peptides for use in thrombus detection

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WO1990015818A1 true WO1990015818A1 (en) 1990-12-27

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EP (1) EP0429626B2 (en)
JP (1) JP2740794B2 (en)
AT (1) ATE137245T1 (en)
DE (1) DE69026685T3 (en)
DK (1) DK0429626T4 (en)
ES (1) ES2087155T5 (en)
GB (2) GB8914020D0 (en)
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Cited By (42)

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WO1992013572A1 (en) * 1991-02-08 1992-08-20 Diatech, Inc. TECHNETIUM-99m LABELED POLYPEPTIDES FOR IMAGING
EP0505385A1 (en) * 1989-11-09 1992-09-30 Smithkline Beecham Corporation Anti-aggregatory peptides containing a mercaptan or sulfide moiety
EP0527056A1 (en) * 1991-08-06 1993-02-10 Antisoma Limited Novel reagent for tumour imaging and therapy
WO1993010747A2 (en) * 1991-11-27 1993-06-10 Diatech, Inc. TECHNETIUM-99m LABELED PEPTIDES FOR IMAGING
WO1993012819A1 (en) * 1992-01-03 1993-07-08 Rhomed Incorporated Protein- and peptide-metal ion pharmaceutical applications
WO1993015770A1 (en) * 1992-02-05 1993-08-19 Mallinckrodt Medical, Inc. Radiolabelled peptide compounds
WO1993023085A1 (en) * 1992-05-21 1993-11-25 Diatech, Inc. TECHNETIUM-99m LABELED PEPTIDES FOR THROMBUS IMAGING
WO1993025244A1 (en) * 1992-06-05 1993-12-23 Diatech, Inc. TECHNETIUM-99m LABELED PEPTIDES FOR IMAGING
WO1994009036A1 (en) * 1992-10-19 1994-04-28 Temple University Of The Commonwealth System Of Higher Education Thrombus detection using radiolabelled disintegrins
WO1994023758A1 (en) * 1993-04-08 1994-10-27 Diatech, Inc. Radiolabeled compounds for thrombus imaging
WO1995012613A1 (en) * 1993-11-01 1995-05-11 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Metal-bonding cystein-free peptides for diagnosis and therapy, process for producing them and pharmaceutical preparations containing these compounds
US5443816A (en) * 1990-08-08 1995-08-22 Rhomed Incorporated Peptide-metal ion pharmaceutical preparation and method
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US6217846B1 (en) 2001-04-17
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DE69026685T2 (en) 1996-10-24
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ES2087155T3 (en) 1996-07-16
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EP0429626A1 (en) 1991-06-05
GB2241243B (en) 1993-01-27

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